1. Technical Field
The present invention relates to pyrazolylmethylamine-piperazine derivatives and their pharmaceutically acceptable salts effective as calcium channel modulators and a method of manufacturing the same. The present invention also relates to the pharmaceutical use of the above compounds as therapeutic treatment of diseases due to their effect as calcium channel modulators.
2. Background Art
Introduction of calcium ions into cells through a voltage-gated calcium channel has been known to mediate a wide scope of cellular and physiological reactions including secretion of hormones, and gene expression. Since 1950s, the flux of calcium ions, expression and physiological importance of transmembrane have been well perceived, and in 1970s, it was made possible to measure the calcium current under voltage-clamp condition (D. Gedualding, R. Gruener, J. Physiolo. 1970, 211, 217-244). In 1980s, neuronal calcium channel, depending on the voltage dependence, was divided into two subtypes of high voltage activity (HVA) Ca2+channel (L, N, P, Q and R type) and low voltage activity (LVA) (T-, L-type) (R, Llinas, Y. Yarom, J. Physiolo. 1981, 315, 549-567, E. Carbone, H. D. Lux, Nature, 1984, 310, 501-502).
Further, LVA-dependent channel, based on its transient signal, was named as ‘T-type calcium channel’, while HVA-dependent channel, based on its long-lasting signal, was named as ‘L-type calcium channel’.
The classification of these calcium channels and their systems thereof are as shown below in the Table 1.
TABLE 1Calcium channelsCav nameα1 subtypeType LCav 1.1α1SCav 1.2α1CCav 1.3α1DCav 1.4α1FType P or QCav 2.1α1AType NCav 2.2α1BType RCav 2.3α1EType TCav 3.1α1GCav 3.2α1HCav 3.3α1I
As shown in the above Table 1, HVA L-type calcium channel is indicated as α1S, α1C, α1D and α1F (Cav 1.1-Cav 1.4) subtypes.
As shown in the above Table 1, HVA L-type calcium channel is indicated as α1S, α1C, α1D and α1F (Cav 1.1-Cav 1.4) subtypes. HVA P-, Q-, N- and R-type calcium channels are indicated as subtypes of (Cav 2.1), α1B (Cav 2.2), and α1E (Cav 2.3), respectively.
LVA T-type calcium channels are indicated as subtypes of α1G, α1H and α1I(Cav 3.1-Cav 3.3). Further, these pore-forming a subtypes can bind to other auxiliary subtypes such as α2 δ, β or γ.
The above voltage-gated ion channels are very closely associated with secretion of neurotransmitters and are mainly discovered in central nervous system, peripheral nervous system and neuroendocrine cells.
All channels used and the neurotransmitters system are somehow involved in pain-signal transmission, and T- and N-type calcium channels are becoming a target for the development of a novel anesthesia.
Pains may be largely divided into acute, chronic and neuropathic pains. Of them, neuropathic pain is initiated or caused by nerve injury, and lesion or dysfunction in the nerves system can result from trauma, viral infection, drug-induced or cancer related condition. It is associated with abnormal sensory phenomena including allododynia and hyperalgesia. It cause sensitization of sensory fibers and awakening of silent nociceptor, and result in reorganization of spinal and cortical circuit which are associated with altered calcium channel expression. Because of the complexity and diversity of the pathophyological mechanisms in neuropathic pain, successful treatment remains difficult to predict and achieve.
Calcium channels are endogenous modulators and have been studied for their roles in relation to multiple neurotransmitter, hormone drugs, antihypertensive drugs, anesthetic drugs, antiarrhythmic drugs, antiepileptic drugs (A. M. Yunker, M. W. McEnery, J. Bioeng. Biomembr. 2003, 35, 533).
Recently, it was shown that N-type (Cav 2.2) and T-type calcium channels are valuable targets for pain treatment by the approval of Prialt® (Elan Pharmaceuticals), their selective blocker developed as a new synthetic drug (Drug Discovery Today, 2006, 11(5), 245-253).
In addition, Cav 2.2 also mediates the release of neurotransmitters from the neurons in the sympathetic nerve system, and antagonists can be used for the treatment of cardiovascular diseases such as hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction and congestive heart failure.
Further, T-type calcium channel is involved in cell development, differentiation and proliferation, cancer growth, sleep, epilepsy, nociception, pain, neuropathic pain, etc., and thus control of the T-type calcium channel has become a target for the regulation of the above.
Further, T-type calcium channel is known to be present in CNS, cardiac and vascular smooth muscle, adrenal cortex, heart, etc., and the inhibitors of the T-type calcium channel is known effective in the treatment of cerebral diseases and cardiovascular diseases such as epilepsy, hypertension, angina pectoris, etc.; {circle around (1)} Hosravani, Houman et al., “Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy”, Annals of Neurology (2005), 57(5), 745-749; {circle around (2)} Vitko, Iuliia et al., “Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel”, Journal of Neuroscience (2005), 25(19), 4844-4855; {circle around (3)} Moosmang, Sven et al., “Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1.2”, Circulation Research (2006), 98(1), 105-110; {circle around (4)} Murielle Veniant et al., “Calcium blockade versus ACE inhibition in clipped and unclipped kidneys of 2K-1C rats”, Kidney International, Vol 46, pp. 421-429; {circle around (5)} Gillian A. Gray et al., “Effects of Calcium blockade on the Aortic Intima in Spontaneously Hypertensive Rats”, Hypertension, Vol 22, No 4 October 1993; {circle around (6)} Santosh K. Mishra et al., “Selective inhibition of T-Type Ca2+ Channels by Ro 40-5967, Circulation Reasearch, Vol 75, No 1 Jul. 1994; {circle around (7)} R J Viskoper et al., “Trial comparing mibefradil and amlodipine”, Journal of Human Hypertention (1997) 11, 387-393.
Recently, the antagonists of T-type calcium channel were reported to be effective in pain treatment. For example, both mibefradil and ethosuximide have shown inhibition of mechanically and thermally evoked neuronal responses in spinal nerve ligation model of neuropathic in rats; {circle around (1)} Barton, Matthew E. et al. “The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil”, European Journal of Pharmacology (2005), 521(1-3), 79-85; {circle around (2)} Flatters, Sarah J. L., “T-type calcium channels: A potential target for the treatment of chronic pain”, Drugs of the Future (2005), 30(6), 573-580; {circle around (3)} Flatters, Sarah J. L. et al. “Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy”, Pain (2004), 109(1-2), 150-161; {circle around (4)} Dogrul, Ahmet et al. “Reversal of experimental neuropathic pain by T-type calcium channel blockers”, Pain (2003), 105(1-2), 159-168; Daesoo Kim et al. “Thalamic Control of Visceral Nociception Mediated by T-Type Ca2+ Channels”, Science Vol 302, 3 Oct. 2003.
USFDA approved or investigated drugs that act on the conventional inhibitors of N-type calcium channel are Gabapentin (Neurontin™) and Ziconotide (Prialt™) as antiepileptic and a neuropathic pain treatment. However, they have a rather low scope of therapeutic efficacies due to factors such as excess administration and patients' characteristics, and also there is a side effect of sedating activity in case of excess dosage.
Of the conventional T-type calcium channel inhibitors, Mibefradil (Ro 40-5967, WO 98/49149) had been used for the treatment of hypertension and angina pectoris. However, it is now withdrawn from market due to drug interactions leading to various adverse effects. It was shown that mibefradil inhibits cytochrome P-450 3A4 and 2D6, enzymes used to metabolize a number of therapeutic agents. Therefore, there is practically no selective T-type calcium channel inhibitor available at present, and thus it is imperative to develop an effective T-type calcium channel antagonist.
Calcium channel inhibitors, due to their close association with neuronal diseases, have been actively studied by large or mid-large sized pharmaceutical firms: e.g., urea derivatives (WO 2006/024260) and heterocyclic compounds (WO 2007/137417 A1) in Neuromed Technology, Inc.; 3,4-dihydroquinazoline derivatives (Korean Pat. No. 0610731), piperazinylalkylisoxazole derivatives (Korean Pat. No. 0616099), piperazinylalkylpyrazole derivatives (Korean Pat. No. 0654328).
Therefore, the inventors of the present invention have made various efforts to develop a novel compound to act in the calcium channel, and found that pyrazolylmethylamine-piperazine derivatives synthesized as a result thereof have excellent antagonistic effect against the T-type calcium channel thereby completing the present invention.